DESCRIPTION

MEVACOR® (lovastatin) is a cholesterol lowering agent
isolated from a strain of Aspergillus terreus. After oral ingestion,
lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding α-
hydroxyacid form. This is a principal metabolite and an inhibitor of
3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase. This enzyme catalyzes
the conversion of HMG-CoA to mevalonate, which is an early and rate limiting
step in the biosynthesis of cholesterol.

Lovastatin is [1S-[1α(R*),3α,7α,8α(2S*,4S*),
8aα]]-1,2,3,7,
8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl
2-methylbutanoate. The empiricalformula of lovastatin is C24H36O5
and its molecular weight is 404.55. Its structural formula is:

Lovastatin is a white, nonhygroscopic crystalline powder
that is insoluble in water and sparingly soluble in ethanol, methanol, and
acetonitrile.

INDICATIONS

Therapy with MEVACOR should be a component of multiple
risk factor intervention in those individuals with dyslipidemia at risk for
atherosclerotic vascular disease. MEVACOR should be used in addition to a diet
restricted in saturated fat and cholesterol as part of a treatment strategy to
lower total-C and LDL-C to target levels when the response to diet and other
nonpharmacological measures alone has been inadequate to reduce risk.

Primary Prevention of Coronary Heart Disease

In individuals without symptomatic cardiovascular
disease, average to moderately elevated total-C and LDL-C, and below average
HDL-C, MEVACOR is indicated to reduce the risk of:

Coronary Heart Disease

MEVACOR is indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment
strategy to lower total-C and LDL-C to target levels.

Hypercholesterolemia

Therapy with lipid-altering agents should be a component
of multiple risk factor intervention in those individuals at significantly
increased risk for atherosclerotic vascular disease due to hypercholesterolemia.
MEVACOR is indicated as an adjunct to diet for the reduction of elevated
total-C and LDL-C levels in patients with primary hypercholesterolemia (Types
IIa and IIb2), when the response to diet restricted in saturated fat
and cholesterol and to other nonpharmacological measures alone has been
inadequate.

Adolescent Patients with Heterozygous Familial
Hypercholesterolemia

MEVACOR is indicated as an adjunct to diet to reduce
total-C, LDL-C and apolipoprotein B levels in adolescent boys and girls who are
at least one year post-menarche, 10-17 years of age, with heFH if after an
adequate trial of diet therapy the following findings are present:

1. LDL-C remains > 189 mg/dL or

Type

Lipoproteins elevated

Lipid Elevations

major

minor

I

chylomicrons

TG

↑→C

I Ia

LDL

C

—

I Ib

LDL, VLDL

C

TG

III (rare)

IDL

C/TG

—

IV

VLDL

TG

↑→C

V (rare)

chylomicrons, VLDL

TG

↑→C

IDL = intermediate-density lipoprotein.

2. LDL-C remains > 160 mg/dL and:

there is a positive family history of premature
cardiovascular disease or

two or more other CVD risk factors are present in the
adolescent patient

General Recommendations

Prior to initiating therapy with lovastatin, secondary
causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus,
hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease,
other drug therapy, alcoholism) should be excluded, and a lipid profile
performed to measure total-C, HDL-C, and TG. For patients with TG less than 400
mg/dL ( < 4.5 mmol/L), LDL-C can be estimated using the following equation:

LDL-C = total-C – [0.2 × (TG) + HDL-C]

For TG levels > 400 mg/dL ( > 4.5 mmol/L), this
equation is less accurate and LDL-C concentrations should be determined by
ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal
despite elevated total-C. In such cases, MEVACOR is not indicated.

The National Cholesterol Education Program (NCEP)
Treatment Guidelines are summarized below:

† CHD, coronary heart disease
†† Some authorities recommend use of LDL-lowering drugs in this category if an
LDL-C level of < 100 mg/dL cannot be achieved by therapeutic lifestyle
changes. Others prefer use of drugs that primarily modify triglycerides and
HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also may call for
deferring drug therapy in this subcategory.
††† Almost all people with 0-1 risk factor have a 10-year risk < 10%; thus,
10-year risk assessment in people with 0-1 risk factor is not necessary.

After the LDL-C goal has been achieved, if the TG is
still ≥ 200 mg/dL, non-HDL-C (total-C minus HDLC) becomes a secondary
target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for
each risk category.

At the time of hospitalization for an acute coronary
event, consideration can be given to initiating drug therapy at discharge if
the LDL-C is ≥ 130 mg/dL (see NCEP Guidelines above).

Since the goal of treatment is to lower LDL-C, the NCEP
recommends that LDL-C levels be used to initiate and assess treatment response.
Only if LDL-C levels are not available, should the total-C be used to monitor
therapy.

Although MEVACOR may be useful to reduce elevated LDL-C
levels in patients with combined hypercholesterolemia and hypertriglyceridemia
where hypercholesterolemia is the major abnormality (Type IIb hyperlipoproteinemia),
it has not been studied in conditions where the major abnormality is elevation
of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or
V).2 The NCEP classification of cholesterol levels in pediatric
patients with a familial history of hypercholesterolemia or premature
cardiovascular disease is summarized below:

Category

Total-C (mg/dL)

LDL-C (mg/dL)

Acceptable

< 170

< 110

Borderline

170-199

110-129

High

≥ 200

≥ 130

Children treated with lovastatin in adolescence should be
re-evaluated in adulthood and appropriate changes made to their
cholesterol-lowering regimen to achieve adult goals for LDL-C.

DOSAGE AND ADMINISTRATION

The patient should be placed on a standard
cholesterol-lowering diet before receiving MEVACOR and should continue on this
diet during treatment with MEVACOR (see NCEP Treatment Guidelines for details
on dietary therapy). MEVACOR should be given with meals.

Adult Patients

The usual recommended starting dose is 20 mg once a day
given with the evening meal. The recommended dosing range of lovastatin is
10-80 mg/day in single or two divided doses; the maximum recommended dose is 80
mg/day. Doses should be individualized according to the recommended goal of therapy
(see NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients
requiring reductions in LDLC of 20% or more to achieve their goal (see INDICATIONS
AND USAGE) should be started on 20 mg/day of MEVACOR. A starting dose of 10
mg of lovastatin may be considered for patients requiring smaller reductions.
Adjustments should be made at intervals of 4 weeks or more. The 10 mg dosage is
provided for information purposes only. Although lovastatin tablets 10 mg are
available in the marketplace, MEVACOR is no longer marketed in the 10 mg
strength.

Cholesterol levels should be monitored periodically and
consideration should be given to reducing the dosage of MEVACOR if cholesterol
levels fall significantly below the targeted range.

Dosage in Patients taking Amiodarone

Adolescent Patients (10-17 years of age) with
Heterozygous Familial Hypercholesterolemia

The recommended dosing range of lovastatin is 10-40 mg/day;
the maximum recommended dose is 40 mg/day. Doses should be individualized
according to the recommended goal of therapy (see NCEP Pediatric Panel
Guidelines4, CLINICAL PHARMACOLOGY, and INDICATIONS
AND USAGE). Patients requiring reductions in LDL-C of 20% or more to
achieve their goal should be started on 20 mg/day of MEVACOR. A starting dose
of 10 mg of lovastatin may be considered for patients requiring smaller reductions.
Adjustments should be made at intervals of 4 weeks or more.

Concomitant Lipid-Lowering Therapy

MEVACOR is effective alone or when used concomitantly
with bile-acid sequestrants (see WARNINGS, Myopathy/Rhabdomyolysis
and PRECAUTIONS: DRUG INTERACTIONS).

Persistent increases of serum transaminases have been
noted (see WARNINGS, Liver Dysfunction). About 11% of patients
had elevations of CK levels of at least twice the normal value on one or more occasions.
The corresponding values for the control agent cholestyramine was 9 percent.
This was attributable to the noncardiac fraction of CK. Large increases in CK
have sometimes been reported (see WARNINGS, Myopathy/Rhabdomyolysis).

Expanded Clinical Evaluation of Lovastatin (EXCEL) Study

MEVACOR was compared to placebo in 8,245 patients with
hypercholesterolemia (total-C 240-300 mg/dL [6.2-7.8 mmol/L]) in the
randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse
experiences reported as possibly, probably or definitely drug-related in ≥ 1%
in any treatment group are shown in the table below. For no event was the
incidence on drug and placebo statistically different.

Placebo
(N = 1663) %

MEVACOR 20 mg q.p.m.
(N = 1642) %

MEVACOR 40 mg q.p.m.
(N = 1645) %

MEVACOR 20 mg b.i.d.
(N = 1646) %

MEVACOR 40 mg b.i.d.
(N = 1649) %

Body As a Whole

Asthenia

1.4

1.7

1.4

1.5

1.2

Gastrointestinal

Abdominal pain

1.6

2.0

2.0

2.2

2.5

Constipation

1.9

2.0

3.2

3.2

3.5

Diarrhea

2.3

2.6

2.4

2.2

2.6

Dyspepsia

1.9

1.3

1.3

1.0

1.6

Flatulence

4.2

3.7

4.3

3.9

4.5

Nausea

2.5

1.9

2.5

2.2

2.2

Musculoskeletal

Muscle cramps

0.5

0.6

0.8

1.1

1.0

Myalgia

1.7

2.6

1.8

2.2

3.0

Nervous System/ Psychiatric

Dizziness

0.7

0.7

1.2

0.5

0.5

Headache

2.7

2.6

2.8

2.1

3.2

Skin

Rash

0.7

0.8

1.0

1.2

1.3

Special Senses

Blurred vision

0.8

1.1

0.9

0.9

1.2

Other clinical adverse experiences reported as possibly,
probably or definitely drug-related in 0.5 to 1.0 percent of patients in any
drug-treated group are listed below. In all these cases the incidence on drug
and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal:
acid regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder
pain, arthralgia; Nervous System/Psychiatric: insomnia, paresthesia; Skin: alopecia,
pruritus; Special Senses: eye irritation.

In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical
Studies), 4.6% of the patients treated up to 48 weeks were discontinued due
to clinical or laboratory adverse experiences which were rated by the
investigator as possibly, probably or definitely related to therapy with
MEVACOR. The value for the placebo group was 2.5%.

In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical
Studies) involving 6,605 participants treated with 20-40 mg/day of MEVACOR
(n=3,304) or placebo (n=3,301), the safety and tolerability profile of the
group treated with MEVACOR was comparable to that of the group treated with placebo
during a median of 5.1 years of follow-up. The adverse experiences reported in AFCAPS/TexCAPS
were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded
Clinical Evaluation of Lovastatin (EXCEL) Study).

Concomitant Therapy

In controlled clinical studies in which lovastatin was
administered concomitantly with cholestyramine, no adverse reactions peculiar
to this concomitant treatment were observed. The adverse reactions that occurred
were limited to those reported previously with lovastatin or cholestyramine.
Other lipid-lowering agents were not administered concomitantly with lovastatin
during controlled clinical studies. Preliminary data suggests that the addition
of gemfibrozil to therapy with lovastatin is not associated with greater reduction
in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical
studies, most of the patients who have developed myopathy were receiving
concomitant therapy with cyclosporine, gemfibrozil or niacin (nicotinic acid).
The combined use of lovastatin with cyclosporine or gemfibrozil should be
avoided. Caution should be used when prescribing other fibrates or
lipid-lowering doses ( ≥ 1 g/day) of niacin with lovastatin (see WARNINGS,
Myopathy/Rhabdomyolysis).

The following effects have been reported with drugs in
this class. Not all the effects listed below have necessarily been associated
with lovastatin therapy.

There have been rare postmarketing reports of cognitive
impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment,
confusion) associated with statin use. These cognitive issues have been reported
for all statins. The reports are generally nonserious, and reversible upon
statin discontinuation, with variable times to symptom onset (1 day to years)
and symptom resolution (median of 3 weeks).

Laboratory Abnormalities

Adolescent Patients (ages 10-17 years)

In a 48-week controlled study in adolescent boys with
heFH (n=132) and a 24-week controlled study in girls who were at least 1 year
post-menarche with heFH (n=54), the safety and tolerability profile of the groups
treated with MEVACOR (10 to 40 mg daily) was generally similar to that of the
groups treated with placebo (seeCLINICAL PHARMACOLOGY, Clinical
Studies in Adolescent Patients and PRECAUTIONS, Pediatric Use).

DRUG INTERACTIONS

CYP3A4 Interactions

Lovastatin is metabolized by CYP3A4 but has no CYP3A4
inhibitory activity; therefore it is not expected to affect the plasma
concentrations of other drugs metabolized by CYP3A4. Strong inhibitors of CYP3A4
(e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin,
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and
erythromycin), and grapefruit juice increase the risk of myopathy by reducing
the elimination of lovastatin. (See CONTRAINDICATIONS, WARNINGS, Myopathy/Rhabdomyolysis,
and CLINICAL PHARMACOLOGY, Pharmacokinetics.)

Interactions With Lipid-Lowering Drugs That Can Cause
Myopathy When Given Alone

The risk of myopathy is also increased by the following
lipid-lowering drugs that are not strong CYP3A4 inhibitors, but which can cause
myopathy when given alone.

Amiodarone: The risk of myopathy/rhabdomyolysis is
increased when amiodarone is used concomitantly with a closely related member
of the HMG-CoA reductase inhibitor class (see WARNINGS, Myopathy/Rhabdomyolysis).

Coumarin Anticoagulants: In a small clinical trial
in which lovastatin was administered to warfarin treated patients, no effect on
prothrombin time was detected. However, another HMG-CoA reductase inhibitor has
been found to produce a less than two-second increase in prothrombin time in
healthy volunteers receiving low doses of warfarin. Also, bleeding and/or
increased prothrombin time have been reported in a few patients taking coumarin
anticoagulants concomitantly with lovastatin. It is recommended that in
patients taking anticoagulants, prothrombin time be determined before starting lovastatin
and frequently enough during early therapy to insure that no significant
alteration of prothrombin time occurs. Once a stable prothrombin time has been
documented, prothrombin times can be monitored at the intervals usually
recommended for patients on coumarin anticoagulants. If the dose of lovastatin
is changed, the same procedure should be repeated. Lovastatin therapy has not
been associated with bleeding or with changes in prothrombin time in patients
not taking anticoagulants.

Colchicine: Cases of myopathy, including
rhabdomyolysis, have been reported with lovastatin coadministered with
colchicine. See WARNINGS, Myopathy/Rhabdomyolysis.

Ranolazine: The risk of myopathy, including
rhabdomyolysis, may be increased by concomitant administration of ranolazine.
See WARNINGS, Myopathy/Rhabdomyolysis.

Propranolol: In normal volunteers, there was no
clinically significant pharmacokinetic or pharmacodynamic interaction with
concomitant administration of single doses of lovastatin and propranolol.

Digoxin: In patients with hypercholesterolemia,
concomitant administration of lovastatin and digoxin resulted in no effect on
digoxin plasma concentrations.

Oral Hypoglycemic Agents: In pharmacokinetic
studies of MEVACOR in hypercholesterolemic noninsulin dependent diabetic
patients, there was no drug interaction with glipizide or with chlorpropamide (see
CLINICAL PHARMACOLOGY, Clinical Studies).

Endocrine Function

Increases in HbA1c and fasting serum glucose levels have
been reported with HMG-CoA reductase inhibitors, including MEVACOR.

HMG-CoA reductase inhibitors interfere with cholesterol
synthesis and as such might theoretically blunt adrenal and/or gonadal steroid
production. Results of clinical trials with drugs in this class have been
inconsistent with regard to drug effects on basal and reserve steroid levels.
However, clinical studies have shown that lovastatin does not reduce basal
plasma cortisol concentration or impair adrenal reserve, and does not reduce
basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor
has been shown to reduce the plasma testosterone response to HCG. In the same
study, the mean testosterone response to HCG was slightly but not significantly
reduced after treatment with lovastatin 40 mg daily for 16 weeks in 21 men. The
effects of HMG-CoA reductase inhibitors on male fertility have not been studied
in adequate numbers of male patients. The effects, if any, on the
pituitarygonadal axis in pre-menopausal women are unknown. Patients treated
with lovastatin who develop clinical evidence of endocrine dysfunction should
be evaluated appropriately. Caution should also be exercised if an HMG-CoA
reductase inhibitor or other agent used to lower cholesterol levels is administered
to patients also receiving other drugs (e.g., spironolactone, cimetidine) that
may decrease the levels or activity of endogenous steroid hormones.

CNS Toxicity

Lovastatin produced optic nerve degeneration (Wallerian
degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent
fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels
about 30 times higher than the mean drug level in humans taking the highest recommended
dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis were also seen in dogs
treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma
drug level (Cmax) similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular
hemorrhage and edema, mononuclear cell infiltration of perivascular spaces,
perivascular fibrin deposits and necrosis of small vessels, were seen in dogs
treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced
plasma drug levels (Cmax) which were about 30 times higher than the mean values
in humans taking 80 mg/day.

Similar optic nerve and CNS vascular lesions have been
observed with other drugs of this class.

Cataracts were seen in dogs treated for 11 and 28 weeks
at 180 mg/kg/day and 1 year at 60 mg/kg/day.

WARNINGS

Myopathy/Rhabdomyolysis

Lovastatin, like other inhibitors of HMG-CoA reductase,
occasionally causes myopathy manifested as muscle pain, tenderness or weakness
with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy
sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary
to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is
increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk
of myopathy/rhabdomyolysis is dose related. In a clinical study (EXCEL) in
which patients were carefully monitored and some interacting drugs were
excluded, there was one case of myopathy among 4933 patients randomized to
lovastatin 20- 40 mg daily for 48 weeks, and 4 among 1649 patients randomized
to 80 mg daily.

All patients starting therapy with MEVACOR, or whose
dose of MEVACOR is being increased, should be advised of the risk of myopathy
and told to report promptly any unexplained muscle pain, tenderness or weakness
particularly if accompanied by malaise or fever or if muscle signs and symptoms
persist after discontinuing MEVACOR. MEVACOR therapy should be discontinued immediately
if myopathy is diagnosed or suspected. In most cases, muscle symptoms and
CK increases resolved when treatment was promptly discontinued. Periodic CK
determinations may be considered in patients starting therapy with MEVACOR or
whose dose is being increased, but there is no assurance that such monitoring
will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on
therapy with lovastatin have had complicated medical histories, including renal
insufficiency usually as a consequence of long-standing diabetes mellitus. Such
patients merit closer monitoring. MEVACOR therapy should be discontinued if markedly
elevated CPK levels occur or myopathy is diagnosed or suspected. MEVACOR
therapy should also be temporarily withheld in any patient experiencing an
acute or serious condition predisposing to the development of renal failure
secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma;
severe metabolic, endocrine, or electrolyte disorders; or uncontrolled
epilepsy.

The risk of myopathy/rhabdomyolysis is increased by
concomitant use of lovastatin with the following:

Strong inhibitors of CYP3A4: Lovastatin, like several
other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4
(CYP3A4). Certain drugs which inhibit this metabolic pathway can raise the
plasma levels of lovastatin and may increase the risk of myopathy. These
include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide
antibiotics erythromycin and clarithromycin, the ketolide antibiotic
telithromycin, HIV protease inhibitors, boceprevir, telaprevir, or the
antidepressant nefazodone. Combination of these drugs with lovastatin is
contraindicated. If short-term treatment with strong CYP3A4 inhibitors is
unavoidable, therapy with lovastatin should be suspended during the course of
treatment (see CONTRAINDICATIONS; PRECAUTIONS: DRUG INTERACTIONS).

Gemfibrozil: The combined use of lovastatin with
gemfibrozil should be avoided.

Other lipid-lowering drugs (other fibrates or ≥ 1
g/day of niacin): Caution should be used when prescribing other fibrates or
lipid-lowering doses ( ≥ 1 g/day) of niacin with lovastatin, as these
agents can cause myopathy when given alone. The benefit of further alterations
in lipid levels by the combined use of lovastatin with other fibrates or niacin
should be carefully weighed against the potential risks of these combinations.

Cyclosporine: The use of lovastatin with
cyclosporine should be avoided.

Danazol, diltiazem, dronedarone or verapamil with higher
doses of lovastatin: The dose of lovastatin should not exceed 20 mg daily
in patients receiving concomitant medication with danazol, diltiazem,
dronedarone, or verapamil. The benefits of the use of lovastatin in patients receiving
danazol, diltiazem, dronedarone, or verapamil should be carefully weighed
against the risks of these combinations.

Amiodarone: The dose of lovastatin should not
exceed 40 mg daily in patients receiving concomitant medication with
amiodarone. The combined use of lovastatin at doses higher than 40 mg daily
with amiodarone should be avoided unless the clinical benefit is likely to
outweigh the increased risk of myopathy. The risk of myopathy/rhabdomyolysis is
increased when amiodarone is used concomitantly with higher doses of a closely
related member of the HMG-CoA reductase inhibitor class.

Colchicine: Cases of myopathy, including
rhabdomyolysis, have been reported with lovastatin coadministered with
colchicine, and caution should be exercised when prescribing lovastatin with colchicine
(see PRECAUTIONS: DRUG INTERACTIONS).

Ranolazine: The risk of myopathy, including
rhabdomyolysis, may be increased by concomitant administration of ranolazine.
Dose adjustment of lovastatin may be considered during coadministration with
ranolazine.

Liver Dysfunction

Persistent increases (to more than 3 times the upper
limit of normal) in serum transaminases occurred in 1.9% of adult patients who
received lovastatin for at least one year in early clinical trials (see ADVERSE
REACTIONS). When the drug was interrupted or discontinued in these
patients, the transaminase levels usually fell slowly to pretreatment levels.
The increases usually appeared 3 to 12 months after the start of therapy with
lovastatin, and were not associated with jaundice or other clinical signs or
symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL
PHARMACOLOGY, Clinical Studies), the incidence of persistent
increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20
mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin.
However, in post-marketing experience with MEVACOR, symptomatic liver disease has
been reported rarely at all dosages (see ADVERSE REACTIONS).

In AFCAPS/TexCAPS, the number of participants with
consecutive elevations of either alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) ( > 3 times the upper limit of normal), over a median
of 5.1 years of follow-up, was not significantly different between the MEVACOR
and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of MEVACOR was
20 mg/day; 50% of the MEVACOR treated participants were titrated to 40 mg/day
at Week 18. Of the 18 participants on MEVACOR with consecutive elevations of
either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day,
while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day.
Elevated transaminases resulted in discontinuation of 6 (0.2%) participants
from therapy in the MEVACOR group (n=3,304) and 4 (0.1%) in the placebo group
(n=3,301).

It is recommended that liver enzyme tests be obtained
prior to initiating therapy with MEVACOR and repeated as clinically indicated.

There have been rare postmarketing reports of fatal and
non-fatal hepatic failure in patients taking statins, including lovastatin. If
serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice
occurs during treatment with MEVACOR, promptly interrupt therapy. If an
alternate etiology is not found do not restart MEVACOR.

The drug should be used with caution in patients who
consume substantial quantities of alcohol and/or have a past history of liver
disease. Active liver disease or unexplained transaminase elevations are contraindications
to the use of lovastatin.

As with other lipid-lowering agents, moderate (less than
three times the upper limit of normal) elevations of serum transaminases have
been reported following therapy with MEVACOR (see ADVERSE REACTIONS).
These changes appeared soon after initiation of therapy with MEVACOR, were often
transient, were not accompanied by any symptoms and interruption of treatment
was not required.

PRECAUTIONS

General

Lovastatin may elevate creatine phosphokinase and
transaminase levels (see WARNINGS and ADVERSE REACTIONS). This
should be considered in the differential diagnosis of chest pain in a patient on
therapy with lovastatin.

Homozygous Familial Hypercholesterolemia

MEVACOR is less effective in patients with the rare
homozygous familial hypercholesterolemia, possibly because these patients have
no functional LDL receptors. MEVACOR appears to be more likely to raise serum
transaminases (see ADVERSE REACTIONS) in these homozygous patients.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 21-month carcinogenic study in mice, there was a
statistically significant increase in the incidence of hepatocellular
carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced
a total plasma drug exposure 3 to 4 times that of humans given the highest
recommended dose of lovastatin (drug exposure was measured as total HMG-CoA
reductase inhibitory activity in extracted plasma). Tumor increases were not
seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2
times that of humans at the 80 mg/day dose. A statistically significant
increase in pulmonary adenomas was seen in female mice at approximately 4 times
the human drug exposure. (Although mice were given 300 times the human dose
[HD] on a mg/kg body weight basis, plasma levels of total inhibitory activity
were only 4 times higher in mice than in humans given 80 mg of MEVACOR.)

There was an increase in incidence of papilloma in the
non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2
times that of humans. The glandular mucosa was not affected. The human stomach
contains only glandular mucosa.

In a 24-month carcinogenicity study in rats, there was a
positive dose response relationship for hepatocellular carcinogenicity in males
at drug exposures between 2-7 times that of human exposure at 80 mg/day (doses
in rats were 5, 30 and 180 mg/kg/day).

An increased incidence of thyroid neoplasms in rats
appears to be a response that has been seen with other HMG-CoA reductase
inhibitors.

A chemically similar drug in this class was administered
to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in
mean serum drug levels approximately 3, 15, and 33 times higher than the mean
human serum drug concentration (as total inhibitory activity) after a 40 mg
oral dose. Liver carcinomas were significantly increased in high dose females
and mid- and high dose males, with a maximum incidence of 90 percent in males.
The incidence of adenomas of the liver was significantly increased in mid- and
high dose females. Drug treatment also significantly increased the incidence of
lung adenomas in mid- and high dose males and females. Adenomas of the
Harderian gland (a gland of the eye of rodents) were significantly higher in
high dose mice than in controls.

No evidence of mutagenicity was observed in a microbial
mutagen test using mutant strains of Salmonella typhimurium with or without rat
or mouse liver metabolic activation. In addition, no evidence of damage to
genetic material was noted in an in vitro alkaline elution assay using rat or
mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome
aberration study in CHO cells, or an in vivo chromosomal aberration assay in
mouse bone marrow.

Drug-related testicular atrophy, decreased
spermatogenesis, spermatocytic degeneration and giant cell formation were seen
in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug
in this class. No drug-related effects on fertility were found in studies with
lovastatin in rats. However, in studies with a similar drug in this class,
there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body
weight, although this effect was not observed in a subsequent fertility study
when this same dose was administered for 11 weeks (the entire cycle of
spermatogenesis, including epididymal maturation). In rats treated with this
same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration
(necrosis and loss of spermatogenic epithelium) was observed. No microscopic
changes were observed in the testes from rats of either study. The clinical
significance of these findings is unclear.

Pregnancy

Pregnancy Category X

Lovastatin has been shown to produce skeletal
malformations in offspring of pregnant mice and rats dosed during gestation at
80 mg/kg/day (affected mouse fetuses/total: 8/307 compared to 4/289 in the control
group; affected rat fetuses/total: 6/324 compared to 2/308 in the control
group). Female rats dosed before mating through gestation at 80 mg/kg/day also
had fetuses with skeletal malformations (affected fetuses/total: 1/152 compared
to 0/171 in the control group). The 80 mg/kg/day dose in mice is 7 times the
human dose based on body surface area and in rats results in 5 times the human
exposure

based on AUC. In pregnant rats given doses of 2, 20, or
200 mg/kg/day and treated through lactation, the following effects were
observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively, compared to 0.6%
in the control group), decreased pup body weights throughout lactation (up to
5%, 8%, and 38%, respectively, below control), supernumerary ribs in dead pups
(affected fetuses/total: 0/7, 1/17, and 11/79, respectively, compared to 0/5 in
the control group), delays in ossification in dead pups (affected fetuses/total:
0/7, 0/17, and 1/79, respectively, compared to 0/5 in the control group) and
delays in pup development (delays in the appearance of an auditory startle
response at 200 mg/kg/day and free-fall righting reflexes at 20 and 200
mg/kg/day).

Direct dosing of neonatal rats by subcutaneous injection
with 10 mg/kg/day of the open hydroxyacid form of lovastatin resulted in
delayed passive avoidance learning in female rats (mean of 8.3 trials to criterion,
compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no effects
on retention 1 week later) at exposures 4 times the human systemic exposure at
80 mg/day based on AUC. No effect was seen in male rats. No evidence of
malformations was observed when pregnant rabbits were given 5 mg/kg/day (doses
equivalent to a human dose of 80 mg/day based on body surface area) or a
maternally toxic dose of 15 mg/kg/day (3 times the human dose of 80 mg/day
based on body surface area).

Rare clinical reports of congenital anomalies following
intrauterine exposure to HMG-CoA reductase inhibitors have been received.
However, in an analysis3 of greater than 200 prospectively followed pregnancies
exposed during the first trimester to MEVACOR or another closely related
HMG-CoA reductase inhibitor, the incidence of congenital anomalies was
comparable to that seen in the general population. This number of pregnancies
was sufficient to exclude a 3-fold or greater increase in congenital anomalies
over the background incidence.

Maternal treatment with MEVACOR may reduce the fetal
levels of mevalonate, which is a precursor of cholesterol biosynthesis.
Atherosclerosis is a chronic process, and ordinarily discontinuation of
lipidlowering drugs during pregnancy should have little impact on the long-term
risk associated with primary hypercholesterolemia. For these reasons, MEVACOR
should not be used in women who are pregnant, or can become pregnant (see CONTRAINDICATIONS).
MEVACOR should be administered to women of child-bearing potential only when
such patients are highly unlikely to conceive and have been informed of the
potential hazards. Treatment should be immediately discontinued as soon as
pregnancy is recognized.

Nursing Mothers

It is not known whether lovastatin is excreted in human
milk. Because a small amount of another drug in this class is excreted in human
breast milk and because of the potential for serious adverse reactions in
nursing infants, women taking MEVACOR should not nurse their infants (seeCONTRAINDICATIONS).

Pediatric Use

Safety and effectiveness in patients 10-17 years of age
with heFH have been evaluated in controlled clinical trials of 48 weeks
duration in adolescent boys and controlled clinical trials of 24 weeks duration
in girls who were at least 1 year post-menarche. Patients treated with
lovastatin had an adverse experience profile generally similar to that of
patients treated with placebo. Doses greater than 40 mg have not been studied
in this population. In these limited controlled studies, there was no
detectable effect on growth or sexual maturation in the adolescent boys or on
menstrual cycle length in girls. See CLINICAL PHARMACOLOGY, Clinical
Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent
Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients
(10-17 years of age) with Heterozygous Familial Hypercholesterolemia.
Adolescent females should be counseled on appropriate contraceptive methods
while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS,
Pregnancy). Lovastatin has not been studied in pre-pubertal patients or
patients younger than 10 years of age.

Geriatric Use

A pharmacokinetic study with lovastatin showed the mean
plasma level of HMG-CoA reductase inhibitory activity to be approximately 45%
higher in elderly patients between 70-78 years of age compared with patients
between 18-30 years of age; however, clinical study experience in the elderly indicates
that dosage adjustment based on this age-related pharmacokinetic difference is
not needed. In the two large clinical studies conducted with lovastatin (EXCEL
and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥ 65 years of age.
Lipid-lowering efficacy with lovastatin was at least as great in elderly
patients compared with younger patients, and there were no overall differences
in safety over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).

OVERDOSE

After oral administration of MEVACOR to mice, the median
lethal dose observed was > 15 g/m².

Five healthy human volunteers have received up to 200 mg
of lovastatin as a single dose without clinically significant adverse experiences.
A few cases of accidental overdosage have been reported; no patients had any
specific symptoms, and all patients recovered without sequelae. The maximum
dose taken was 5-6 g.

Until further experience is obtained, no specific
treatment of overdosage with MEVACOR can be recommended.

The dialyzability of lovastatin and its metabolites in
man is not known at present.

Pregnancy and lactation (see PRECAUTIONS, Pregnancy
and Nursing Mothers). Atherosclerosis is a chronic process and the
discontinuation of lipid-lowering drugs during pregnancy should have little
impact on the outcome of long-term therapy of primary hypercholesterolemia.
Moreover, cholesterol and other products of the cholesterol biosynthesis
pathway are essential components for fetal development, including synthesis of
steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase
such as MEVACOR to decrease the synthesis of cholesterol and possibly other
products of the cholesterol biosynthesis pathway, MEVACOR is contraindicated
during pregnancy and in nursing mothers. MEVACOR should be administered to
women of childbearing age only when such patients are highly unlikely to
conceive. If the patient becomes pregnant while taking this drug, MEVACOR
should be discontinued immediately and the patient should be apprised of the
potential hazard to the fetus (see PRECAUTIONS, Pregnancy).

CLINICAL PHARMACOLOGY

The involvement of low-density lipoprotein cholesterol
(LDL-C) in atherogenesis has been welldocumented in clinical and pathological studies,
as well as in many animal experiments. Epidemiological and clinical studies
have established that high LDL-C and low high-density lipoprotein cholesterol
(HDLC) are both associated with coronary heart disease. However, the risk of
developing coronary heart disease is continuous and graded over the range of
cholesterol levels and many coronary events do occur in patients with total
cholesterol (total-C) and LDL-C in the lower end of this range.

MEVACOR has been shown to reduce both normal and elevated
LDL-C concentrations. LDL is formed from very low-density lipoprotein (VLDL)
and is catabolized predominantly by the high affinity LDL receptor. The
mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of
VLDL-C concentration, and induction of the LDL receptor, leading to reduced
production and/or increased catabolism of LDL-C. Apolipoprotein B also falls
substantially during treatment with MEVACOR. Since each LDL particle contains
one molecule of apolipoprotein B, and since little apolipoprotein B is found in
other lipoproteins, this strongly suggests that MEVACOR does not merely cause
cholesterol to be lost from LDL, but also reduces the concentration of
circulating LDL particles. In addition, MEVACOR can produce increases of variable
magnitude in HDL-C, and modestly reduces VLDL-C and plasma triglycerides (TG)
(see Tables II-IV under Clinical Studies). The effects of MEVACOR on
Lp(a), fibrinogen, and certain other independent biochemical risk markers for
coronary heart disease are unknown.

MEVACOR is a specific inhibitor of HMG-CoA reductase, the
enzyme which catalyzes the conversion of HMG-CoA to mevalonate. The conversion
of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for
cholesterol.

Pharmacokinetics

Lovastatin is a lactone which is readily hydrolyzed in
vivo to the corresponding α-hydroxyacid, a strong inhibitor of HMG-CoA
reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic
studies of the α-hydroxyacid metabolites (active inhibitors) and,
following base hydrolysis, active plus latent inhibitors (total inhibitors) in
plasma following administration of lovastatin.

Following an oral dose of 14C-labeled lovastatin in man,
10% of the dose was excreted in urine and 83% in feces. The latter represents
absorbed drug equivalents excreted in bile, as well as any unabsorbed drug.
Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites)
peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours postdose.
Absorption of lovastatin, estimated relative to an intravenous reference dose,
in each of four animal species tested, averaged about 30% of an oral dose. In
animal studies, after oral dosing, lovastatin had high selectivity for the
liver, where it achieved substantially higher concentrations than in non-target
tissues. Lovastatin undergoes extensive first-pass extraction in the liver, its
primary site of action, with subsequent excretion of drug equivalents in the
bile. As a consequence of extensive hepatic extraction of lovastatin, the
availability of drug to the general circulation is low and variable. In a
single dose study in four hypercholesterolemic patients, it was estimated that
less than 5% of an oral dose of lovastatin reaches the general circulation as
active inhibitors. Following administration of lovastatin tablets the
coefficient of variation, based on between-subject variability, was
approximately 40% for the area under the curve (AUC) of total inhibitory activity
in the general circulation.

The major active metabolites present in human plasma are
the α-hydroxyacid of lovastatin, its 6'-hydroxy
derivative, and two additional metabolites. Peak plasma concentrations of both
active and total inhibitors were attained within 2 to 4 hours of dose
administration. While the recommended therapeutic dose range is 10 to 80 mg/day,
linearity of inhibitory activity in the general circulation was established by a
single dose study employing lovastatin tablet dosages from 60 to as high as 120
mg. With a once-a-day dosing regimen, plasma concentrations of total inhibitors
over a dosing interval achieved a steady state between the second and third
days of therapy and were about 1.5 times those following a single dose. When
lovastatin was given under fasting conditions, plasma concentrations of total
inhibitors were on average about two-thirds those found when lovastatin was
administered immediately after a standard test meal.

In a study of patients with severe renal insufficiency
(creatinine clearance 10-30 mL/min), the plasma concentrations of total
inhibitors after a single dose of lovastatin were approximately two-fold higher
than those in healthy volunteers.

In a study including 16 elderly patients between 70-78
years of age who received MEVACOR 80 mg/day, the mean plasma level of HMG-CoA
reductase inhibitory activity was increased approximately 45% compared with 18
patients between 18-30 years of age (see PRECAUTIONS, Geriatric Use).

Although the mechanism is not fully understood,
cyclosporine has been shown to increase the AUC of HMG-CoA reductase
inhibitors. The increase in AUC for lovastatin and lovastatin acid is
presumably due, in part, to inhibition of CYP3A4.

The risk of myopathy is increased by high levels of
HMG-CoA reductase inhibitory activity in plasma. Strong inhibitors of CYP3A4
can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase
the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS: DRUG INTERACTIONS).

Lovastatin is a substrate for cytochrome P450 isoform 3A4
(CYP3A4) (see PRECAUTIONS: DRUG INTERACTIONS). Grapefruit juice
contains one or more components that inhibit CYP3A4 and can increase the plasma
concentrations of drugs metabolized by CYP3A4. In one study1, 10
subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen
concentrate diluted with one rather than 3 cans of water) three times daily for
2 days and an additional 200 mL double-strength grapefruit juice together with
and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third
day. This regimen of grapefruit juice resulted in a mean increase in the serum
concentration of lovastatin and its α-hydroxyacid metabolite (as measured
by the area under the concentration-time curve) of 15-fold and 5-fold, respectively
[as measured using a chemical assay — high performance liquid chromatography].
In a second study, 15 subjects consumed one 8 oz glass of single-strength
grapefruit juice (one can of frozen concentrate diluted with 3 cans of water)
with breakfast for 3 consecutive days and a single dose of 40 mg lovastatin in
the evening of the third day. This regimen of grapefruit juice resulted in a
mean increase in the plasma concentration (as measured by the area under the
concentration-time curve) of active and total HMG-CoA reductase inhibitory
activity [using an enzyme inhibition assay both before (for active inhibitors)
and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold,
respectively, and of lovastatin and its α-hydroxyacid metabolite [measured
using a chemical assay — liquid chromatography/tandem mass spectrometry —
different from that used in the first1 study] of 1.94-fold and 1.57-fold,
respectively. The effect of amounts of grapefruit juice between those used in
these two studies on lovastatin pharmacokinetics has not been studied.

TABLE I: The Effect of Other Drugs on Lovastatin
Exposure When Both Were Co-administered

Number of Subjects

Dosing of Coadministered Drug or Grapefruit Juice

Dosing of Lovastatin

AUC Ratio* (with / without coadministered drug) No Effect = 1.00

Lovastatin

Lovastatin acid†

Gemfibrozil

11

600 mg BID for 3 days

40 mg

0.96

2.80

Itraconazole*

12

200 mg QD for 4 days

40 mg on Day 4

> 36§

22

10

100 mg QD for 4 days

40 mg on Day 4

> 14.8§

15.4

Grapefruit Juice1¶(high dose)

10

200 mL of double-strength TID#

80 mg single dose

15.3

5.0

Grapefruit Juice¶ (low dose)

16

8 oz (about 250 mL) of single-strengthÞ for 4 days

40 mg single dose

1.94

1.57

Cyclosporine

16

Not describedβ

10 mg QD for 10 days

5- to 8-fold

NDa

Number of Subjects

Dosing of Coadministered Drug or Grapefruit Juice

Dosing of Lovastatin

AUC Ratio* (with / without coadministered drug)
No Effect = 1.00

Total Lovastatin acide

Diltiazem

10

120 mg BID for 14 days

20 mg

3.57e

* Results based on a chemical assay.
† Lovastatin acid refers to the α-hydroxyacid of lovastatin.
‡ The mean total AUC of lovastatin without itraconazole phase could not be
determined accurately. Results could be representative of strong CYP3A4
inhibitors such as ketoconazole, posaconazole, clarithromycin, telithromycin,
HIV protease inhibitors, and nefazodone.
§ Estimated minimum change.
¶ The effect of amounts of grapefruit juice between those used in these two
studies on lovastatin pharmacokinetics has not been studied.
# Double-strength: one can of frozen concentrate diluted with one can of water.
Grapefruit juice was administered TID for 2 days, and 200 mL together with
single dose lovastatin and 30 and 90 minutes following single dose lovastatin
on Day 3.
Þ Single-strength: one can of frozen concentrate diluted with 3 cans of water.
Grapefruit juice was administered with breakfast for 3 days, and lovastatin was
administered in the evening on Day 3.
β Cyclosporine-treated patients with psoriasis or post kidney or heart
transplant patients with stable graft function, transplanted at least 9 months
prior to study.a ND = Analyte not determined.e Lactone converted to acid by hydrolysis prior to analysis. Figure represents
total unmetabolized acid and lactone.

Clinical Studies in Adults

MEVACOR has been shown to be highly effective in reducing
total-C and LDL-C in heterozygous familial and non-familial forms of primary
hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen
within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks.
The response was maintained during continuation of therapy. Single daily doses
given in the evening were more effective than the same dose given in the
morning, perhaps because cholesterol is synthesized mainly at night.

In multicenter, double-blind studies in patients with
familial or non-familial hypercholesterolemia, MEVACOR, administered in doses
ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo. MEVACOR
consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C
ratio and LDLC/ HDL-C ratio. In addition, MEVACOR produced increases of
variable magnitude in HDL-C, and modestly decreased VLDL-C and plasma TG (see
Tables II through IV for dose response results). The results of a study in
patients with primary hypercholesterolemia are presented in Table II.

MEVACOR was compared to cholestyramine in a randomized
open parallel study. The study was performed with patients with
hypercholesterolemia who were at high risk of myocardial infarction. Summary
results are presented in Table III.

MEVACOR was studied in controlled trials in hypercholesterolemic
patients with well-controlled noninsulin dependent diabetes mellitus with
normal renal function. The effect of MEVACOR on lipids and lipoproteins and the
safety profile of MEVACOR were similar to that demonstrated in studies in nondiabetics.
MEVACOR had no clinically important effect on glycemic control or on the dose requirement
of oral hypoglycemic agents.

The Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS), a double-blind, randomized, placebo-controlled, primary
prevention study, demonstrated that treatment with MEVACOR decreased the rate
of acute major coronary events (composite endpoint of myocardial infarction,
unstable angina, and sudden cardiac death) compared with placebo during a
median of 5.1 years of follow-up. Participants were middle-aged and elderly men
(ages 45-73) and women (ages 55-73) without symptomatic cardiovascular disease
with average to moderately elevated total-C and LDL-C, below average HDL-C, and
who were at high risk based on elevated total-C/HDL-C. In addition to age, 63%
of the participants had at least one other risk factor (baseline HDL-C < 35
mg/dL, hypertension, family history, smoking and diabetes).

AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men,
997 women) based on the following lipid entry criteria: total-C range of
180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤ 45 mg/dL for men
and ≤ 47 mg/dL for women, and TG of ≤ 400 mg/dL. Participants were
treated with standard care, including diet, and either MEVACOR 20-40 mg daily
(n= 3,304) or placebo (n= 3,301). Approximately 50% of the participants treated
with MEVACOR were titrated to 40 mg daily when their LDL-C remained > 110
mg/dL at the 20-mg starting dose.

MEVACOR reduced the risk of a first acute major coronary
event, the primary efficacy endpoint, by 37% (MEVACOR 3.5%, placebo 5.5%;
p < 0.001; Figure 1). A first acute major coronary event was defined as
myocardial infarction (54 participants on MEVACOR, 94 on placebo) or unstable
angina (54 vs. 80) or sudden cardiac death (8 vs. 9). Furthermore, among the
secondary endpoints, MEVACOR reduced the risk of unstable angina by 32% (1.8
vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%; p=0.002),
and of undergoing coronary revascularization procedures (e.g., coronary artery
bypass grafting or percutaneous transluminal coronary angioplasty) by 33% (3.2
vs. 4.8%; p=0.001). Trends in risk reduction associated with treatment with
MEVACOR were consistent across men and women, smokers and non-smokers,
hypertensives and non-hypertensives, and older and younger participants.
Participants with ≥ 2 risk factors had risk reductions (RR) in both acute
major coronary events (RR 43%) and coronary revascularization procedures (RR
37%). Because there were too few events among those participants with age as
their only risk factor in this study, the effect of MEVACOR on outcomes could
not be adequately assessed in this subgroup.

Figure 1 : Acute Major Coronary Events (Primary
Endpoint)

Atherosclerosis

In the Canadian Coronary Atherosclerosis Intervention
Trial (CCAIT), the effect of therapy with lovastatin on coronary
atherosclerosis was assessed by coronary angiography in hyperlipidemic
patients. In the randomized, double-blind, controlled clinical trial, patients
were treated with conventional measures (usually diet and 325 mg of aspirin
every other day) and either lovastatin 20-80 mg daily or placebo. Angiograms
were evaluated at baseline and at two years by computerized quantitative
coronary angiography (QCA). Lovastatin significantly slowed the progression of
lesions as measured by the mean change per-patient in minimum lumen diameter
(the primary endpoint) and percent diameter stenosis, and decreased the
proportions of patients categorized with disease progression (33% vs. 50%) and
with new lesions (16% vs. 32%).

In a similarly designed trial, the Monitored
Atherosclerosis Regression Study (MARS), patients were treated with diet and
either lovastatin 80 mg daily or placebo. No statistically significant
difference between lovastatin and placebo was seen for the primary endpoint
(mean change per patient in percent diameter stenosis of all lesions), or for
most secondary QCA endpoints. Visual assessment by angiographers who formed a
consensus opinion of overall angiographic change (Global Change Score) was also
a secondary endpoint. By this endpoint, significant slowing of disease was
seen, with regression in 23% of patients treated with lovastatin compared to
11% of placebo patients.

In the Familial Atherosclerosis Treatment Study (FATS),
either lovastatin or niacin in combination with a bile acid sequestrant for 2.5
years in hyperlipidemic subjects significantly reduced the frequency of progression
and increased the frequency of regression of coronary atherosclerotic lesions
by QCA compared to diet and, in some cases, low-dose resin.

The effect of lovastatin on the progression of
atherosclerosis in the coronary arteries has been corroborated by similar
findings in another vasculature. In the Asymptomatic Carotid Artery Progression
Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis
was assessed by B-mode ultrasonography in hyperlipidemic patients with early
carotid lesions and without known coronary heart disease at baseline. In this
double-blind, controlled clinical trial, 919 patients were randomized in a 2 x
2 factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin.
Ultrasonograms of the carotid walls were used to determine the change per
patient from baseline to three years in mean maximum intimal-medial thickness
(IMT) of 12 measured segments. There was a significant regression of carotid
lesions in patients receiving lovastatin alone compared to those receiving
placebo alone (p=0.001). The predictive value of changes in IMT for stroke has
not yet been established. In the lovastatin group there was a significant
reduction in the number of patients with major cardiovascular events relative
to the placebo group (5 vs. 14) and a significant reduction in all-cause
mortality (1 vs. 8).

Eye

There was a high prevalence of baseline lenticular
opacities in the patient population included in the early clinical trials with
lovastatin. During these trials the appearance of new opacities was noted in
both the lovastatin and placebo groups. There was no clinically significant
change in visual acuity in the patients who had new opacities reported nor was
any patient, including those with opacities noted at baseline, discontinued
from therapy because of a decrease in visual acuity.

A three-year, double-blind, placebo-controlled study in
hypercholesterolemic patients to assess the effect of lovastatin on the human
lens demonstrated that there were no clinically or statistically significant differences
between the lovastatin and placebo groups in the incidence, type or progression
of lenticular opacities. There are no controlled clinical data assessing the
lens available for treatment beyond three years.

Clinical Studies in Adolescent Patients

Efficacy of Lovastatin in Adolescent Boys with
Heterozygous Familial Hypercholesterolemia

In a double-blind, placebo-controlled study, 132 boys
10-17 years of age (mean age 12.7 yrs) with heterozygous familial
hypercholesterolemia (heFH) were randomized to lovastatin (n=67) or placebo (n=65)
for 48 weeks. Inclusion in the study required a baseline LDL-C level between
189 and 500 mg/dL and at least one parent with an LDL-C level > 189 mg/dL.
The mean baseline LDL-C value was 253.1 mg/dL (range: 171-379 mg/dL) in the
MEVACOR group compared to 248.2 mg/dL (range: 158.5-413.5 mg/dL) in the placebo
group. The dosage of lovastatin (once daily in the evening) was 10 mg for the
first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.

The mean achieved LDL-C value was 190.9 mg/dL (range:
108-336 mg/dL) in the MEVACOR group compared to 244.8 mg/dL (range: 135-404
mg/dL) in the placebo group.

Efficacy of Lovastatin in Post-Menarchal Girls with
Heterozygous Familial Hypercholesterolemia

In a double-blind, placebo-controlled study, 54 girls
10-17 years of age who were at least 1 year post-menarche with heFH were
randomized to lovastatin (n=35) or placebo (n=19) for 24 weeks. Inclusion in
the study required a baseline LDL-C level of 160-400 mg/dL and a parental
history of familial hypercholesterolemia. The mean baseline LDL-C value was
218.3 mg/dL (range: 136.3-363.7 mg/dL) in the MEVACOR group compared to 198.8
mg/dL (range: 151.1-283.1 mg/dL) in the placebo group. The dosage of lovastatin
(once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg
thereafter.

The mean achieved LDL-C value was 154.5 mg/dL (range:
82-286 mg/dL) in the MEVACOR group compared to 203.5 mg/dL (range: 135-304
mg/dL) in the placebo group.

The safety and efficacy of doses above 40 mg daily have
not been studied in children. The long-term efficacy of lovastatin therapy in
childhood to reduce morbidity and mortality in adulthood has not been established.

PATIENT INFORMATION

Patients should be advised about substances they should
not take concomitantly with MEVACOR and be advised to report promptly
unexplained muscle pain, tenderness, or weakness particularly if accompanied by
malaise or fever or if muscle signs and symptoms persist after discontinuing
MEVACOR (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should
also be advised to inform other physicians prescribing a new medication that
they are taking MEVACOR.

It is recommended that liver enzymes be checked before
starting therapy, and if signs or symptoms of liver injury occur. All patients
treated with MEVACOR should be advised to report promptly any symptoms that may
indicate liver injury, including fatigue, anorexia, right upper abdominal
discomfort, dark urine or jaundice.

Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.